Nanogels—porous nanoscale hydrogel networks—are a class of nanomaterials with tunable chemical properties that facilitate targeting and delivery to specific tissues. They are intrinsically porous and can be loaded with small drugs or macromolecules by physical entrapment, covalent conjugation or controlled self-assembly. The porosity of nanogels protect the drugs they carry from degradation and environmental hazards; hence, nanogels can be used as drug delivery agents and contrast agents for medical imaging.
Fucoidans are a class of sulfated, fucose-rich polymers that can be found, for example, in brown macroalgae. Fucoidans have been reported to have anticoagulant, antiviral, anti-inflammatory, and anticancer activities, as well as high affinity to P-selectin. P-selectin is an inflammatory cell adhesion molecule responsible for leukocyte recruitment and platelet binding. It is expressed constitutively in endothelial cells where it is stored in intracellular granules (Weibel-Palade bodies). Upon endothelial activation with endogenous cytokines or exogenous stimuli such as ionizing radiation, P-selectin translocates to the cell membrane and into the lumen of blood vessels. P-selectin expression has been found to increase significantly in the vasculature of human lung, breast, and kidney cancers. P-selectin has been shown to facilitate the process of metastasis by coordinating the interaction between cancer cells, activated platelets and activated endothelial cells.
It has been unexpectedly found that P-selectin is expressed in stroma and cancer cells in may human tumors, as well as in vasculature. Only one previous report describes P-selectin expression in cancer cells—a metastatic pancreatic tumor cell line. The phenomenon of tumor cell expression of endothelial-specific adhesion molecules such as ICAM-1, VCAM-1, CD31/PECAM-1 and VE-cadherin has been applied to various types of cancer cells and associated with increased metastasis and poor patient prognosis.
The direct administration of fucoidan as a treatment for tumors or metastases can be ineffective, due to toxicity limitations and lack of drug targeting. Disseminated tumors are poorly accessible to nanoscale drug delivery systems due to the vascular barrier, which prevents sufficient extravasation at the tumor site. Strategies to target leaky vasculature via the enhanced permeability and retention (EPR) effect have shown little efficacy on avascular tumors and small metastases.
The clinical potential of nanomedicines has not yet been fulfilled in part due to the endothelium barrier which limits the extravasation of nanoparticles from the circulation into solid tumors. Passive targeting mechanisms such as the enhanced permeability and retention “EPR” effect show preclinical efficacy. Yet the effect is less effective in small tumors and metastases. Endothelial cells (EC) in the neovasculature are promising targets due to their genetic stability and exposure to the circulation. Nanoparticle drug carriers targeting the neovasculature are currently under clinical development, however, targeted delivery of therapeutic agents to micro-metastases or tumors lacking neovasculature remains an enduring challenge.
A nanogel containing fucoidan has been produced by chemical acetylation of the hydroxyl groups of fucoidan, rendering it amphipilic and able to form nanoparticles loaded with doxorubicin (Lee et al., Carbohydrate Polymers 95 (2013) 606-614). However, by acetylating the hydroxyl groups of fucose, specific affinity of the drug-containing nanogel to P-selectin is eliminated, thereby adversely affecting the ability of the nanogel to target cancer and other diseases associated with P-selectin.
There exists a need for a fucoidan-based nanogel that has a specific affinity to P-selectin to treat cancer and other diseases and conditions associated with P-selectin.